Project Summary: IgE-mediated food allergy, particularly to peanuts (PN) and tree nuts (TN), is a major health problem in the United States, affecting approximately 4% of children and up to 2% of adults. Most children allergic to PN do not outgrow this condition and as many as half of these must also avoid other foods, particularly TN, such as walnuts (WN) and cashew nuts (CN). Recent progress with early administration of peanuts should reduce new cases of severe although there are limitations such as compliance. Oral immunotherapy (OIT), sublingual immunotherapy (SLIT), and epicutaneous immunotherapy (EPIT), although not yet FDA approved, hold significant promise. Subcutaneous injection of omalizumab (anti-IgE; Xolair) appears to be a useful adjunct for decreasing reactivity during OIT. Unfortunately, these approaches are not successful for all patients and, even when successful, have limitations regarding compliance and unpredictable breakthrough. Thus, there is a significant, unmet need for new oral treatments, used alone or in combination with those now in development. We propose to develop novel peptides that mimic conformational epitopes and to bind to Ara h 2 and Ara h 6 for the purposes of inhibiting binding of IgE and potentially for immunotherapy. Among the 17 known PN allergens, the 2S albumins Ara h 2 and Ara h 6 are the most potent for eliciting IgE-mediated mast cell activation. Our overarching concept is that we can use current and evolving knowledge of the molecular details of how these potent allergens elicit an allergic reaction and advances in the design of stable structured peptides, to develop novel therapies, and to identify mechanisms whereby allergens interact with IgE. We will present evidence that there are key IgE-binding, linear and conformational epitopes of Ara h 2 and Ara h 6. We hypothesize that these epitopes can be targeted using a molecular approach. We propose design a set of novel linear and 3D mimetic peptides that high affinity for allergen- specific IgE, low affinity for IgG4 and the ability to interfere with IgE/IgE receptor cross-linking. These stable, high affinity peptides can ultimately be used for desensitization and potentially for direct therapy, either alone or in combination with existing approaches (e.g. OIT or EPIT).